PROJECT DESCRIPTION One of the central problems in human genetics is to understand the molecular basis of complex disease. Of the millions of DNA positions that vary among humans, which sites actually impact human phenotypes and disease? It is now clear that an enormous number of variants across the genome affect any given complex trait. In recent work we have proposed that these most of these variants affect disease risk by acting as trans-regulators of core disease genes. However at present we have very little knowledge of trans-regulatory networks, and traditional trans-eQTL mapping is underpowered even with thousands of samples. In this project we propose to implement a CRISPR-based screening approaching for measuring trans-regulators of genes of interest in primary T cells. We will evaluate the strength of this approach as an experimental alternative to trans-eQTL mapping.